The long-range objective of this project is to elucidate the basic mechanisms of drug allergy in man. The prototype chosen for study is penicillin hypersensitivity, the most prevalent drug allergy. An ongoing clinical study evaluates the usefulness of skin testing with penicillin derivatives in assessing the risk of immediate allergic reactions. For the major penicilloyl antigenic determinant, we have developed a radioallergosorbent test (RAST) for measurement of IgE in the sera of allergic patients, and two radioimmunoassay procedures for penicilloyl IgG. These serological assays are being applied to immune response studies in patients receiving penicillins therapeutically. Protocols are proposed to investigate the possible technical, metabolic, and genetic explanations for an apparent restriction of penicilloyl immune responsiveness. This project will pursue similar studies of the immune response to heterologous insulins administered to patients with diabetes mellitus. The frequency of IgG and IgE immune responsiveness will be determined, and the persistance of such antibodies will be evaluated in an effort to understand the pathogenesis of insulin allergy and insulin resistance. Additional studies to be pursued with these techniques include evaluation of cross-reactivity among penicillin and cephalosporin antibiotics and the development of serological tests for minor determinant penicillin antibodies. Patients with insulin or penicillin allergy who are subjected to desensitization will be studied in detail including serial IgG and IgE antibody determinations and evaluation of changes in basophil and skin sensitivity. The role of IgG antibody in protecting against IgE mediated allergic reactions will be explored. The goal of this work is better understanding of the mechanisms of clinical desensitization to insulin and penicillin, and of protective mechanisms which prevent clinical reactions in patients who have mounted a drug-specific IgE response.